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Continuation of certolizumab pegol with Or Without MTX in RA patients achieving sustained remissioN and low disease activity (CROWN study)

Continuation of certolizumab pegol with Or Without MTX in RA patients achieving sustained remissioN and low disease activity (CROWN study)

86

Overall in the Full Analysis Set (FAS) of 84 patients, 40 assigned to certolizumab pegol (CZP) monotherapy group or 44 assigned to CZP plus methotrexate (CZP+MTX) group. In the CZP monotherapy group and the CZP+MTX group, 34 (85.0%) and 37 (84.1%) of the patients were female, respectively. The mean age (+- standard deviation) was 63.9 +- 12.4 years and 60.9 +- 12.1 years, respectively. The median baseline Simplified Disease Activity Index (SDAI) with interquartile range was 0.75 (0.05-2.85) in the CZP monotherapy group and 1.70 (0.75-3.40) in the CZP+MTX group. The mean patient VAS score at baseline (+- standard deviation) was 10.0 +- 11.6 in the CZP monotherapy group and 15.7 +- 13.8 in the CZP + MTX group, and there was statistically significant difference between the groups. However, there were no statistically significant differences in other patient backgrounds, including duration of disease, RA Steinbrocker stage classification, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and Health Assessment Questionnaire (HAQ) scores between the groups.

Among the 86 enrolled patients, 42 were assigned to the CZP monotherapy group and 44 to the CZP+MTX group. All patients began the protocol therapy. All of 86 patients were included in the safety analysis set. However, two patients were excluded from FAS due to lacking efficacy data at any point after starting the protocol therapy, resulting in FAS of 84 (40 assigned to CZP monotherapy group and 44 assigned to CZP+MTX group). In addition, one patient of prohibited concomitant medication use, six patients of discontinuation with SDAI =< 11 at all time points up to discontinuation, and seven patients censored before 52 weeks of treatment due to study discontinuation were excluded. This resulted in the exclusion of a total of 14 cases, leaving 70 patients were included in the Per-Protocol Set (PPS) (34 patients in the CZP monotherapy group and 36 patients in the CZP+MTX group).

According to Article 13 of the Clinical Trials Act, there were 14 events of 13 patients (13/86,15.1%) reported to the certified review board (CRB) as disease or the like suspected of being due to the conduct of specified clinical trials stated in the trial plan of such specified clinical trials. There were 13 events in 12 patients (12/42, 28.6%), including ten relapse or exacerbation of rheumatoid arthritis (RA), one arthritis, one eczema, and one joint pain in the CZP monotherapy group. All were non-serious. In the CZP+MTX group, there were one event in one patient (1/44, 2.3%), palmoplantar pustulosis, which was non-serious. Fifteen patients (15/42, 35.7%) in the CZP monotherapy group experienced adverse events (AEs), including 11 RA, one duodenal ulcer, one pulmonary tuberculosis, one arthralgia, one arthritis, one eczema, and one rash. In the CZP+MTX group, 6 patients (6/44, 13.6%) experienced AEs, including one diverticulitis, one pneumonia, one RA, one fibromyalgia, one pruritus, and one palmoplantar pustulosis. Two patients (2/42, 4.8%) in the CZP monotherapy group experienced CZP-related AEs, including one pulmonary tuberculosis and one eczema. In the CZP+MTX group, five patients (5/44, 11.4%) experienced CZP-related AEs, including one diverticulitis, one pneumonia, one RA, one pruritus, and one palmoplantar pustulosis. As for serious AEs, pulmonary tuberculosis occurred in one patient (1/42, 2.4%) in the CZP monotherapy group and pneumonia in one patient (1/44, 2.3%) in the CZP+MTX group.

Primary endpoint: In the FAS, the 1-year low disease activity (LDA) maintenance rate was 72.5% (29 out of 40 patients) in the CZP monotherapy group and 93.2% (41 out of 44 patients) in the CZP+MTX group. The difference in maintenance rates between the groups was -20.7%, with a 90% confidence interval (CI) ranging from -33.6% to -7.7%. The one-tailed score test with a pre-specified non-inferiority margin of 10% indicated no significant difference (p=0.912). In a sensitivity analysis, in which the patients of discontinuation were invalidated, the 1-year LDA maintenance rate in the CZP monotherapy group was 60.0% (24 out of 40 patients) compared to 75.0% (33 out of 44 patients) in the CZP+MTX group. The difference in maintenance rates between the groups was -15.0% (90% CI -31.7% to 1.7%), with the one-sided score test showing no significant difference (p=0.689), against a non-inferiority margin of 10%. In the PPS analysis, the 1-year LDA maintenance rate was 70.6% (24 out of 34 patients) in the CZP monotherapy group and 91.7% (33 out of 36 patients) in the CZP+MTX group. The difference in maintenance rates between the groups was -21.1% (90% CI -35.9% to -6.2%), with the one-sided score test showing no significant difference (p=0.890), against a non-Primary endpoint: In the FAS, the 1-year low disease activity (LDA) maintenance rate was 72.5% (29 out of 40 patients) in the CZP monotherapy group and 93.2% (41 out of 44 patients) in the CZP+MTX group. The difference in maintenance rates between the groups was -20.7%, with a 90% confidence interval (CI) ranging from -33.6% to -7.7%. The one-tailed score test with a pre-specified non-inferiority margin of 10% indicated no significant difference (p=0.912). In a sensitivity analysis, in which the patients of discontinuation were invalidated, the 1-year LDA maintenance rate in the CZP monotherapy group was 60.0% (24 out of 40 patients) compared to 75.0% (33 out of 44 patients) in the CZP+MTX group. The difference in maintenance rates between the groups was -15.0% (90% CI -31.7% to 1.7%), with the one-sided score test showing no significant difference (p=0.689), against a non-inferiority margin of 10%. In the PPS analysis, the 1-year LDA maintenance rate was 70.6% (24 out of 34 patients) in the CZP monotherapy group and 91.7% (33 out of 36 patients) in the CZP+MTX group. The difference in maintenance rates between the groups was -21.1% (90% CI -35.9% to -6.2%), with the one-sided score test showing no significant difference (p=0.890), against a non-inferiority margin of 10% (p=0.890). In the analysis stratified by SDAI at baseline, difference in 1-year LDA maintenance rate was -29.0% for SDAI 3.3 or less and 5.1% for SDAI >3.3, respectively, and there was difference between these groups in 1-year LDA maintenance rate for SDAI 3.3 or less. Furthermore, in the analysis stratified by rheumatoid factor at baseline, difference in 1-year LDA maintenance rate was -1.6% for rheumatoid factor below 22.1 and -39.4% for those above 22.1, respectively. There was difference between these groups in 1-year LDA maintenance rate for rheumatoid factor above 22.1. Secondary endpoints: The 1-year SDAI remission rate was 52.5% (21 out of 40 patients) in the CZP monotherapy group and 70.5% (31 out of 44 patients) in the CZP+MTX group. The difference in the remission rates between the groups was -18.0% (95% CI -38.5% to 2.6%). The 1-year Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) remission rate was 50.0% (20 out of 40 patients) in the CZP monotherapy group and 75.0% (33 out of 44 patients) in the CZP+MTX group. The difference in remission rates between the groups was -25.0% (95% CI -45.1% to -4.9%). Out of 77 patients (37 in the CZP monotherapy group and 40 in the CZP+MTX group) excluding 7 who discontinued follow-up by 52 weeks due to early study termination, 12 in the CZP monotherapy group and 6 in the CZP+MTX group discontinued the protocol treatment within 1 year. The cumulative 52-week continuation rate was 67.6% in the CZP monotherapy group and 85.0% in the CZP+MTX group. The hazard ratio (CZP monotherapy group versus CZP+MTX group) was 2.62 (95% CI 0.98 to 6.99), indicating a significant difference in the duration of the 1-year protocol treatment between these groups (Log-rank test p=0.045).

This study was a multicenter randomized, parallel-group, comparative analysis focused on patients with RA. These patients, whose disease activity was initially controlled using a combination of CZP and MTX, were assessed to determine if CZP alone could maintain disease control after discontinuing MTX. The primary measure was the 1-year rate of maintaining LDA, using this as an index. There was no significant difference in the one-tailed score test, with a 10% non-inferiority margin.

Feb. 28, 2025

No

No

https://jrct.mhlw.go.jp/latest-detail/jRCTs071190001

Miyazaki Yusuke

Hospital of the University of Occupational and Environmental Health, Japan

1-1 Iseigaoka Yahatanishi-ku Kitakyushu-shi Fukuoka, Japan

yuppy0316@med.uoeh-u.ac.jp

Miyazaki Yusuke

Hospital of the University of Occupational and Environmental Health, Japan

1-1 Iseigaoka Yahatanishi-ku Kitakyushu-shi Fukuoka, Japan

+81-93-603-1611

yuppy0316@med.uoeh-u.ac.jp

Complete

April. 01, 2019

Interventional

randomized controlled trial

open(masking not used)

active control

parallel assignment

treatment purpose

1) Patients aged over 16 years (at the time of informed consent)
2) Patients diagnosed with rheumatoid arthritis (RA) under the 1987 American College of Rheumatology (ACR) or 2010 ACR/European League Against Rheumatism (EULAR) criteria
3) Patients who have been receiving combination therapy with MTX ( over 6 mg/week) and CZP for 24 weeks before enrollment of the study
4) Patients who showed SDAI less than 11 at any visit for over 3 months before enrollment without taking any steroids
5) Patients who provided written informed consent

Patients judged by the investigator to be unsuitable for participants in the study

Both

Rheumatoid arthritis

Patients retaining LDA with the combination of CZP and MTX are randomized to two groups consisting of patients who continue MTX at the same doses or discontinue MTX. The effects of both groups are compared 1 year after starting study.

Control group
combination therapy with subcutaneous CZP (200 mg in every 2 weeks or 400 mg in every 4 weeks) and oral MTX (at the same dose before starting the protocol treatment) given for 52 weeks of the protocol treatment, or until the time of discontinuation.

Intervention group
monotherapy with CZP (200 mg in every 2 weeks or 400 mg in every 4 weeks) given for 52 weeks of the protocol treatment, or until the time of discontinuation.

The discontinuation criteria for the study are as follows:
1) When subjects requested to discontinue the treatment
2) When the principal investigator or subinvestigator considered that the therapy should be discontinued due to adverse (drug) events
3) When a subject turned out not to fulfil the inclusion criteria or meets the exclusion criteria after starting the study
4) When RA relapses, defined as SDAI over 11, were observed at two consecutive visits
5) When the principal investigator or subinvestigator considered continuation of the study is inappropriate for reasons other than above

Percentage of patients with SDAI less than 11 at 12, 24, and 52 weeks after starting the study

SDAI remission rate at 52 weeks after starting the study
DAS28-ESR remission rate at 52 weeks after starting the study
Duration of protocol therapy
Change from baseline in the mTSS at 52 weeks after starting the study

+81-744-29-8835

Mar. 20, 2019

none